Drug interaction and incompatibility in veterinary practice

Practical XIV

Types of drug interactions*

1. Outside of the body (extracorporal)

Physical or chemical incompatibility

2. Inside of the body (intracorporal)

+ additive/potentiation v. synergism

(e.g. CNS inhibitors/antibacterial agents)

- Therapeutic incompatibility

Pharmacodynamic interaction

Pharmacokinetic (ADME) interaction

*Not only drug-drug or drug-excipient interactions exist, but feed-drug, drug-toxin interactions and interactions with endogen metabolites are possible.

Drug interactions outside the body

• Physical incompatibility

Change of the original dose form (consistency, shape, viscosity, etc.)

Mixing, dilution of infusion and injections (e.g. ivermectin)

Change in pH (tetracyclines + alkaline solutions)

Mixing of lipophilic and hydrophilic ointments, suppositorybases

Ionization (ratio of dissociated to undissociated compound, e.g. mixing of pentobarbital with xylazine, opioids, ketamine injections)

Eutectics e.g. menthol + camphor + (aspirin) v. antipyrin + sulfur

• Chemical incompatibility

Several type of chemical reactions, e.g.: Oxydation

Reduction

Hydroxylation

Double replacement

Insoluble complex formation: Ca2+ + oxytetracycline

Pharmacodynamic interaction• Receptorial

Competitive (direct)agonist vs. antagonist or partial agonist(e.. fentanyl vs. butorphanol)

Non-competitive (non-direct) Same organ/tissue same receptor (allosteric, irreversible) Same organ/tissue different receptors (Danger, increasing

effect!)- Aminoglycosides + non-depolarizing muscle relaxants- H1-antihistamines + hypnosedatives- Combination of antihypertensives- Combination of antiarrhythmics

Physiological (e.g. adrenergic vs. cholinergic, androgens vs. oestrogens)

• Non-receptorialChelators, adsorbents, antacids (e.g. EDTA, activated carbon, MgO)

(see PK/absorption interactions also)

Pharmacokinetic interactions, absorption

• Inhibited by:

- complex with ions (amoxicillin, tetracyclines, fluoroquinolones),

- adsorbents, adstringents, antacids, plant fibers

- lipophilic excipient (grizeofulvin: increase!)

- muscarinic agents (shorter transition time)

Pharmacokinetic interactions, distribution

Competition in binding to transporting plasma proteins during transport processes:

e.g. coumarin-type anticoagulants, digoxin NSAID

Substance Bound

(%)

Unbound

(%)

Digoxin 77 23

Gentamicin 50 50

Teophylline 86 14

Phenytoin 22 78

Diazepam 4 96

Phenylbutazone 5 95

Furosemide 5 95

• The most common type of pharmacokinetic druginteraction.

• During drug metabolism active substancestrasformed into inactive (sometimes toxic) metabolites.

• The amount of metabolites formed and the rate of conversion are influenced by the concomitant administration of other drugs.

• This may reduce or increase the duration of action of the medicines.

Pharmacokinetic interactions,

biotransformation

Drug metabolism, overview

• Phase I. reactions: Convert parent compound into a more polar (hydrophilic) metabolite by adding or unmaskingfunctional groups

• Phase II. reactions: Conjugation with endogenous substrate to further increase aqueous solubility

• Formation of less reactive metabolites• Exemptions: prodrug, toxic, carcinogenic metabolites

• The same processes are taking place during drug metabolism as the body's own biochemical and physiological processes• Medicines are often synthetic endogenous substrates: steroid

hormones, bile acids

• Drugs resemble the natural compound

• Aliphatic, aromatic hydroxylation

• Alkylation (Methylation)

• Dealkylation

• Ring cyclization

• N-carboxylation

• Dimerization

• Transamidation

• Isomerization

• Decarboxylation

• Epoxide, nitro group, N-oxide reduction

• Hydrolysis

Catalysts of phase I reactions: CYP450 (see later),

MAOs, FMOs, esterases, alcohol-dehydrogenases,

aldehyde-dehydrogenases, etc.

Phase I reactions

Phase II., conjugation reactionsReaction Enzyme

(where)Cosubstrate Substrate

Glucuronidconjugation

UDP-glucuronosyltransferase(ER-membrane)

UDP-glucuronicacid

OH-, COOH-: morphine, chloramphenicol, oxazepam, diclofenac, furosemide

Sulphate-conjugation

Sulfotransferase(cytosol)

3′-phosphoadenosine 5′-

phosphosulfate (PAPS)See above, paracetamol, propofol, thyroxine

Glutation-conjugation

Glutathion-S-transferase(cytosol)

Glutathion Electrophil C-: epoxides

Amino acidconjugation

Acyl-CoA -synthetase + amino acid-N-acyltransferase (mitochondrion)

ATP + CoA + amino acid(glycine, glutamine, ornithine, arginine)

COOH-: salicylic acid,benzoic acid, nicotinic acid

Acetylation N-acetyltransferase (cytosol)

Acetil-CoA NH2-: sulfamethoxazole, sulfamethazine

Methylation Methyltransferase(cytosol)

S-adenosylmethionine OH-, N-, SH-:histamine, nicotine

CYP450 enzyme system• Heme thiolate type monooxygenases

• NADH or NADPH

• NADPH-cytochrome-P450 reductase

• O2

• SER membrane-bound

• Liver tissue

• Classification of CYP450 gene family according to DNA sequence homology:

Family >40% Subfamily >55% Gene>90%

CYP2C3

Cytochrome P450

CYP450 enzyme systemCYP family

Substrate Inducers Inhibitors

CYP1 caffeine, theophylline,paracetamol,albendazole, thiabendazole, mebendazole

omeprazolecharcoal-broiledmeat, smoking, dioxin,indole-3-carbinole(cabbage, broccoli)

ciprofloxacinefluvoxamincimetidineacyclovir

CYP2 phenytoin, warfarin,omeprazole, diazepam,antidepressants,β-blockers,halothane, paracetamol

phenobarbital,rifampin,ethanol,isoniazide

terbinafine, fluconazole, omeprazole

CYP3 benzodiazepinesclarithromycin, erithromycin,steroide hormones, codeine, fentanyl

phenobarbital,phenytoincarbamazepinerifampindexamethasone

pleuromutilines,macrolide antibioticsGrapefruit-juice: naringenin, bergamottin,azole antifungals: e.g. ketoconazole

CYP-catalysed reactions

diazepam nordiazepam

N-dealkylation:

CYP-catalysed reactions

propofol 4-hydroxy-propofol

Hydroxylation:

CYP-catalysed reactions

thiopental pentobarbital

S

Oxidative desulfuration:

CYP-catalysed reactions

Dehydrogenation:

paracetamol N-Acetyl-p-benzoquinone imine

Determination of CYP450 activity, in vivo

Treatment• Whole liver, • Liver lobe,

• lobus caudatus• Liver biopsy

Determination of CYP450 activity,

centrifugation

ex vivo

Treatment

in vivo

Determination of CYP450 activity,

Isolation of primer hepatocytes

Organ culture

Tissue slice

Tissue culture

ex vivoinvitro

Determination of CYP450 activity, in vitro

Test substances: stimulatory- and inhibitory agents, active substances of drugs

Luminescentsubsrate (specificfor CYP

isoenzyme)

Culture medium + detection reagent

Determination of CYP450 activity withluminometry:

in vitro, in vivo, ex vivo

Proluciferin substrate

0

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Kontroll Fenobarbitál Ketokonazol

Rela

tiv

e L

um

inescen

ce U

nit

CYP3A6

***

*** ***

0

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Kontroll Fenobarbitál Ketokonazol

Rela

tiv

e L

um

inescen

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CYP3A6

***

*

***

CYP450 activity:in vivo and in vitro

CYP-mediated interactions

• Phenobarbital + many anti-infectious agents (macrolides, lincosamides, chloramphenicol, griseofulvin) - decreased efficacy

• Phenobarbital + corticosteroids (prednisolone) / progestagens(proligestone): decreased efficacy

• Rifampicin + antiarrhythmics / beta-receptor antagonists (metoprolol, nadolol) / anticoagulants / corticosteroids: decreased efficacy

• Pphenylbutazone + barbiturates: increased duration of action

• Ionophore coccidiostats (monensin, narasin, salinomycin) + tiamulin / valnemulin: chicken, turkey

• Cimetidine + lidocaine: increased level

• Monepantel induces CYP1A, 2B, 2C, 2E, 3A activity and expression of the 3A24 gene in sheep.

Effect of tylosin, monensin and tiamulin on CYP activity in chickens

0

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0 1 2 3 4 5 6

RLU

mM

CYP1A4

tiamulin

tylosin

monensin

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0 1 2 3 4 5 6

RLU

mM

CYP2C23

tiamulin

tylosin

monensin

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0 1 2 3 4 5 6

RLU

mM

CYP2C45

tiamulin

tylosin

monensin

Quantification of metabolites formed

• Spectrophotometry, ELISA (high LOD, LOQ)

• Luminometry/Fluorimetry

• Indirect-RIA

• GC

• HPLC

• LC-MS

Pharmacokinetic interactions, elimination

- urine pHbasic acidic : procaine, antihistamines,

caffeine, pethidine

basic acidic : barbiturates, sulfonamides

- interaction in tubular active transport

probenecid NSAID blood level

penicillin half-life